PROJECT SUMMARY/ABSTRACT Although conceptualized as a neurodevelopmental disorder with present research primarily focused on infants and children, autism spectrum disorder (ASD) has increasingly been recognized as a lifelong condition with the potential to have a detrimental impact on adult functioning and quality of life. Point 1: Based on preliminary findings that individuals with ASD may be particularly susceptible to neurodegenerative issues during aging1,2, the proposed studies will test the central hypothesis that cerebellum and basal ganglia are selectively disrupted in mid-aged and older adults with ASD, and this disruption is associated with neuromotor impairments and probable increased clinical features of cerebellar ataxia and Parkinsonism. Using laboratory tests sensitive in detecting these subcortical structural alterations, we will clarify the extent to which neuromotor performance of Romberg stances, quick step initiation, sit-to-stance balance, and goal-directed finger pointing is impacted in adults with ASD aged 40 to 60 years relative to age-, sex- and IQ-matched healthy controls. An innovative two- compartment free-water diffusion magnetic resonance imaging (FWdMRI) will be applied to quantify the neuronal density of cerebellar lobules and basal ganglia nuclei and axonal density of cerebellar peduncles to determine whether these subcortical structures are selectively disrupted in adults with ASD and whether these alterations underpin neuromotor issues. We propose the following specific aims: Aim 1: Determine cerebellar and basal- ganglia related neuromotor deficits in ASD. Aim 2: Determine cerebellar and basal-ganglia structural alterations in ASD. Our group is uniquely qualified to undertake this critical project as it includes investigators with expertise and experience in sensorimotor neurophysiology in ASD, ASD diagnosis, aging and movement disorders, MRI physics and research, and biostatistics. Support from this FOA will allow the team to calculate the success rate of data collection, effect size, and statistic power and to demonstrate the feasibility of recruitment in adults with ASD in order to plan for a full-scale R01 project. This proposal is scientifically 'high risk' as it will be the first to systematically quantify the neuromotor deficits in adults with ASD at the levels of behavior and brain anatomy and to determine the relationships between these impairments and clinical features of cerebellar ataxia and Parkinsonism. If successful, this work holds the greatest promises to be ‘high rewarding’ as it will identify new biobehavioral targets that can be tracked to understand, monitor, and treat conditions related to aging in ASD.

PROJECT NARRATIVE Adults with autism spectrum disorder (ASD) aged 40-60 years are highly susceptible in developing neurodegenerative diseases. The goal of this study is to uniquely identify structural cerebellar and basal ganglia changes and their contributions to neuromotor impairments in adults with ASD. The proposed studies will provide fundamental insights into the aging process in ASD to inform diagnosis, management, and monitoring strategies.